Pharmaceutical compositions of hydrophobic surface-modified active substance microparticles for inhalation

ABSTRACT

The invention provides microparticles for use in a pharmaceutical composition for pulmonary administration, each microparticle comprising a particle of an active substance having, on its surface, particles of a hydrophobic material suitable for delaying the dissolution of the active substance. The invention also provides a method for making the microparticles.

The invention relates to pharmaceutical compositions for inhalation.

Pulmonary administration is known for the delivery of drugs for thetreatment of respiratory conditions such as asthma and is receivingincreasing attention as a route for the delivery of systemic drugs suchas insulin. Known devices for the administration of drugs to therespiratory system include pressurised metered dose inhalers (pMDI's)and dry powder inhalers (DPI's).

In pulmonary administration, the size of the active particles is ofgreat importance in determining the site of the absorption. In orderthat the particles be carried deep into the lungs, the particles must bevery fine, for example having a mass median aerodynamic diameter of lessthan 10 μm. Particles having aerodynamic diameters greater than 10 μmare likely to impact the walls of the throat and generally do not reachthe lung. Particles having aerodynamic diameters in the range of 5 μm to0.5 μm will generally be deposited in the respiratory bronchioleswhereas smaller particles having aerodynamic diameters in the range of 2to 0.05 μm are likely to be deposited in the alveoli.

In an attempt to improve the flow of the powder, dry powders for use indry powder inhalers often include particles of an excipient materialmixed with the fine particles of active material. Such particles ofexcipient material may be coarse, for example having a mass medianaerodynamic diameter greater than 90 μm, (such coarse particles arereferred to as carrier particles) or they may be fine.

Propellant-based formulations for use with pressurised metered doseinhalers are also known and are widely used.

It has long been desired to develop pharmaceutical formulations in whichthe pharmaceutically active substance is released over a comparativelylong period of time in order to maintain the concentration of the activesubstance in the blood at a desired level for a comparatively longerperiod of time. An associated benefit is an increase in patientcompliance with the dosing regime brought about by reducing the numberof, and/or the frequency of, the administrations necessary to maintainthe concentration of the active substance in the blood at the desiredlevel.

Delayed release compositions have been developed for delivery of drug tothe gastrointestinal tract and some such compositions are commerciallyavailable. Systems for the controlled delivery of an active substancethrough the skin have also been developed.

Known techniques for preparing controlled release formulations can becategorised into one of two types. The first type involves theapplication of a barrier substance, in solution, to the activesubstance, for example, by spray drying or precipitation. The secondtype involves condensation of a barrier substance, from a vapour of thebarrier substance, onto particles of active material.

However, there remains a need to develop a delayed release compositionfor pulmonary administration having satisfactory properties.

The present invention provides microparticles for use in apharmaceutical composition for pulmonary administration, eachmicroparticle comprising a particle of active substance having, on itssurface, particles of a hydrophobic material suitable for delaying thedissolution of the active substance.

The term “microparticles” as used herein refers to particles of a sizesuitable for pulmonary administration or smaller, for example, having anMMAD of 10 μm or less.

The microparticles of the invention are able to release the activesubstance over a longer period than similarly-sized particles of theactive substance alone and therefore a reduced frequency ofadministration, preferably only once a day or less, is possible.Furthermore, that delayed release of the active substance provides alower initial peak of concentration of the active substance which mayresult in reduced side effects associated with the active substance.

The hydrophobic material will be suitable for delaying the dissolutionof the active substance in an aqueous medium. A test method fordetermining whether a particular hydrophobic substance is suitable fordelaying that dissolution is given below. The test may also be used fordetermining the extent of the reduction in the rate of dissolution andreferences herein to a reduction in that rate are to be understood asreferring to the test given below. An alternative measure ofhydrophobicity is the contact angle. The contact angle of a material isthe angle between a liquid droplet and the surface of the material overwhich it spreads. The hydrophobic material preferably has a contactangle of more than 90°, more preferably more than 95° and mostpreferably more than 100°. The skilled person will be aware of suitablemethods of measuring the contact angle for a particular substance.

The hydrophobic material will be pharmacologically acceptable foradministration to the lungs in the amounts required according to theinvention. Preferably, the hydrophobic material will not be stickybecause sticky substances will tend to reduce dispersibility of thepowder. Preferably, the hydrophobic material is a solid at roomtemperature.

Preferably, the hydrophobic material is one which is suitable forpromoting the dispersal of the active particles on actuation of aninhaler.

The particles of hydrophobic material may include a combination of oneor more substances. Preferably, all of those substances are hydrophobicmaterials but it is within the scope of the invention for thehydrophobic particles to include one or more substances which are notthemselves hydrophobic, as long as the particles also contain materialswhich are hydrophobic in sufficient quantity that the mixture ishydrophobic as defined herein.

Preferably, the hydrophobic material is a naturally occurring animal orplant substance.

Advantageously, the hydrophobic material includes one or more compoundsselected from hydrophobic amino acids and derivatives thereof, andhydrophobic peptides and polypeptides having a molecular weight from0.25 to 1000 Kda, and derivatives thereof. Hydrophobic amino acids,peptides or polypeptides and derivatives of peptides or polypeptides areoften physiologically acceptable.

It is advantageous for the hydrophobic material to comprise ahydrophobic amino acid. The additive material may comprise one or moreof any of the following amino acids: tyrosine, tryptophan, glutamicacid, aspartic acid, leucine, isoleucine, lysine, valine, methionine,phenylalanine. The additive may be a salt or a derivative of an aminoacid, for example, aspartame or acesulfame K. Preferred derivativesinclude salts, esters and amides. Preferably, the additive particlesconsist substantially of an amino acid, more preferably of leucine,advantageously L-leucine. The D- and DL-forms may also be used.

The hydrophobic material may have a limited degree of water solubility.This helps absorption of the hydrophobic substance by the body when thehydrophobic material reaches the lower lung. The hydrophobic materialmay, however, be insoluble in water, for example, the hydrophobicmaterial may be magnesium stearate.

The hydrophobic material may comprise lecithin or a phospholipid or aderivative thereof such as an ester, amide or salt.

Preferably, the hydrophobic material comprises or consists of a C₁₀ toC₂₂ carboxylic acid which may be linear or branched, saturated orunsaturated or a derivative thereof such as an ester, amide or a salt.

Advantageously, the hydrophobic material comprises a metal stearate, ora derivative thereof, for example, sodium stearyl fumarate or sodiumstearyl lactylate. Preferably, the hydrophobic material comprises ametal stearate. For example, magnesium stearate, calcium stearate,sodium stearate or lithium stearate. Preferably, the hydrophobicmaterial comprises magnesium stearate.

The hydrophobic material may include or consist of one or more surfaceactive materials, in particular materials that are surface active in thesolid state, which may be water soluble to some degree, for example,lecithin, in particular soya lecithin, or substantially water insoluble,for example, solid state fatty acids such as oleic acid, behenic acid,or derivatives (such as esters and salts) thereof such as glycerylbehenate. Specific examples of such materials are:phosphatidylethanolamines, phosphatidylcholines, phosphatidylglycerolsand other examples of natural synthetic lung surfactants; triglyceridessuch as Dynsan 118 and Cutina HR; and sugar esters in general,hydrogenated oils which are solid at room temperature, sorbitan esterswhich are solid at room temperature, cetyl stearyl alcohol and cetylalcohol.

The hydrophobic material preferably comprises one or more materialsselected from the group consisting of hydrophobic amino acids,lecithins, phospholipids, metal stearates (especially magnesiumstearate), sodium stearyl fumarate, solid state fatty acids and glycerylbehenate.

The optimum amount of hydrophobic material will depend on, inter alia,the chemical composition and other properties of the hydrophobicmaterial and upon the nature and particle size of the active material.In general, the amount of hydrophobic material in the compositeparticles will be not more than 90% by weight, based on the total weightof the microparticles.

Advantageously, the microparticles comprise not more than 80%, morepreferably not more than 60%, more preferably not more than 40% byweight of the hydrophobic material, based on the total weight of themicroparticles. The microparticles will usually comprise at least 0.01%by weight of the hydrophobic material and will preferably comprise atleast 1%, more preferably at least 5% and optionally at least 15% byweight of the hydrophobic material, based on the total weight of themicroparticles.

The microparticles advantageously comprise at least 0.1% by weight,preferably at least 1%, more preferably at least 10%, moreadvantageously at least 50% and especially advantageously at least 90%by weight of the active substance based on the total weight of themicroparticles. The microparticles will, in general, not comprise morethan 99.9% by weight of the active substance based on the total weightof the microparticles.

The mass median aerodynamic diameter of the microparticles is preferablynot more than 10 μm, and advantageously not more than 5 μm, morepreferably not more than 3 μm and may be less than 1 μm. Accordingly,advantageously at least 90% by weight of the microparticles have adiameter of not more than 10 μm, advantageously not more than 5 μm,preferably not more than 3 μm and optionally not more than 1 μm.Advantageously, the microparticles will be the size of a suitable sizefor inhalation to the desired part of the lung, for example, having anMMAD in the range of 3 to 0.1 μm for absorption in the deep lung, 5 to0.5 μm for absorption in the respiratory bronchioles, 10 to 2 μm fordelivery to the higher respiratory system and 2 to 0.05 μm for deliveryto the alveoli. Accordingly, advantageously at least 90% by weight ofthe microparticles have an aerodynamic diameter in the range of 3 to 0.1μm, preferably 5 to 0.5 μm, advantageously 1.0 to 2 μm, and especiallyadvantageously 2 to 0.05 μm. The MMAD of the microparticles will notnormally be lower than 0.1 μm.

Alternatively, the microparticles may have diameters lower than thepreferred range but may be present in the form of agglomeratedmicroparticles, those agglomerated microparticles having mass medianaerodynamic diameters in one of the ranges described above. The term“agglomerated microparticles” refers to particles which consist of morethan one microparticle, those microparticles being adhered to eachother. For example, an agglomerated microparticle of diameter 5 μm mayconsist of a large number of microparticles each having a diameter of 1μm or less, adhered together. The agglomerated microparticles willnormally be sufficiently stable that they do not break up duringadministration to the patient. The microparticles may also have on theirsurfaces a film forming material which may help to bind them together inan agglomerate.

Advantageously, the microparticles have at least a partial coating of afilm-forming material which acts as a further barrier to the release ofthe active substance. The film-forming material will be pharmaceuticallyacceptable for administration to the lungs in amounts required inaccordance with the invention. Suitable film forming materials aredisclosed in U.S. Pat. No. 5,738,865 and U.S. Pat. No. 5,612,053 andinclude polysaccharides such as xanthan gum. Other preferredpolysaccharides include derivatives of xanthan gum, such as deacylatedxanthan gum, the carboxymethyl ether, the propylene glycol eater and thepolyethylene glycol esters and galactomannan gums, which arepolysaccharides composed solely of mannose and galactose. Locust beangum, which has a higher ratio of mannose to the galactose, is especiallypreferred as compared to other galactomannans such as guar andhydroxypropyl guar.

Other naturally occurring polysaccharide gums known to those skilled inthe food and pharmaceutical arts are also useful as the delayed releasecarrier of the invention. Such polysaccharides include alginic acidderivatives, carageenans, tragacanth, acacia, karaya, the polyethyleneglycol esters of these gums, chitin, chitosan, mucopolysaccharides,konjac, starch, substituted starches, starch fragments, dextrins,British gums having a molecular weight of about 10,000 daltons, dextransand the like. The starches can either be in native form i.e., ungelledstarches such as potato, corn, rice, banana, etc., or gelled starches orsemi-synthetic starches.

Starch and starch fragments are especially preferred polysaccharides andthe combination of xanthan gum with locust bean gum is an especiallypreferred gum combination.

Other film-forming materials include pharmaceutically acceptablesynthetic polymeric compounds such as polyvinylpyrrolidone (PVP) andprotein materials such as albuimin and gelatin.

The film-forming material may be present in an amount of from 99% toabout 10%, preferably from 50% to about 10%, by weight based on thetotal weight of the microparticles, that is, the total weight of theactive substance and the hydrophobic material.

Preferably, the microparticles are such that, when inhaled, the activesubstance exerts its pharamacological effect over a period significantlygreater (for example, greater by at least 20%, more preferably at least50%) than the period over which the active substance exerts itspharmacological effect when inhaled alone (that is, when an equivalentquantity of the active substance is inhaled in the form of inhalableparticles consisting of the active substance).

The invention will be of particular value where the active substance isone which exerts its pharmacological effect over a limited period andwhere, for therapeutic reasons, it is desired to extend that period.Preferably, the microparticles comprise an active substance that, wheninhaled, exerts its pharmacological effect over a period of less than 12hours, the microparticles being such that the active substance exertsits pharmacological effect over a period greater than 12 hours. Theduration of the pharmacological effect for any particular activesubstance can be measured by methods known to the skilled person andwill be based on the administration of the dose of that substance thatis recognised as being optimal for that active substance in thecircumstances. For example, where the active substance is salbutamolsulphate, the duration of the pharmacological effect will be measured bymeasuring the effect of administering a dose of themedically-recommended quantity of salbutamol upon the patients'respiratory volume. The means of measuring the duration of the periodover which a particular active substance exerts its pharmacologicaleffect will depend upon the nature of the active substance and mayinclude, for example, the monitoring of variables relating to inhalationsuch as FEV₁ level where the active substance is one which exerts apharmacological effect over the pulmonary system, for example,salbutamol. Further examples include the monitoring of blood sugarlevels where the active substance is insulin or the subjectivemonitoring of pain relief by the patient where the active substance isan analgesic. Where it is not possible to unambiguously monitor theduration of the pharmacological effect of the active substance, forexample, because that duration depends from instance to instance uponexternal factors beyond experimental control, the duration of thepharmacological effect may be assumed to be the same as the durationover which the active substance has the desired concentration in arelevant bodily fluid. Methods for measuring such concentrations areknown to the skilled person. Advantageously, the microparticles are suchthat the active substance exerts its pharmacological effect over aperiod of at least 15 hours, preferably at least 24 hours.

Preferably, the microparticles are such that the rate of dissolution ofthe active substance (when tested according to the procedure givenbelow) is no greater than 80%, more preferably no greater than 70%,advantageously no greater than 50% and most preferably no greater than30%, of the rate of dissolution of particles of the active substance.

Optionally, the microparticles do not comprise an effective amount of anantimuscarinic substance. Optionally, the microparticles do not comprisean effective amount of glycopyrrolate. Optionally, the microparticles donot consist of a mixture of micronised glycopyrrolate and magnesiumstearate in the ratio of 75:25 by mass. Suitable active substancesinclude materials for therapeutic and/or prophylactic use. Activesubstances which may be included in the formulation include thoseproducts which are usually administered orally by inhalation for thetreatment of disease such as respiratory disease, for example,β-agonists.

The active substance may be a β₂-agonist, for example, a compoundselected from terbutaline, salbutamol, salmeterol and formetorol. Ifdesired, the microparticles may comprise more than one of those activesubstances, provided they are compatible with one another underconditions of storage and use. Preferably, the active substance may besalbutamol sulphate. References herein to any active agent is to beunderstood to include any physiologically acceptable derivative. In thecase of the β₂-agonists mentioned above, physiologically acceptablederivatives include especially salts, including sulphates.

The active substance may be a steroid, which may be beclomethasonedipropionate or may be fluticasone. The active substance may be acromone which may be sodium cromoglycate or nedocromil. The activesubstance may be a leukotriene receptor antagonist.

The active substance may be a carbohydrate, for example heparin.

The active substance may advantageously comprise a pharmacologicallyactive substance for systemic use and advantageously is capable of beingabsorbed into the circulatory system via the lungs. For example, theactive substance may be a peptide or a polypeptide such as Dnase,leukotrienes or insulin. Preferably, the active substance is abiological macromolecule, for example, a polypeptide, a protein, or aDNA fragment. The active substance may be selected from the groupconsisting of insulin, human growth hormone, cytokines, cyclosporin,interferon, gonadotrophin agonists and antagonists, erythropoietin,leptin, antibodies, vaccines, antisense oligonucleotides, calcitonin,somotastatin, parathyroid hormone, alpha-1-antitrypsin, Factor 7, Factor8, Factor 9, and estradiol. Advantageously the active substance isselected from the group consisting of insulin, human growth hormone,cytokines, cyclosporin, interferon, gonadotrophin agonists andantagonists, erythropoietin, leptin, antibodies, vaccines and antisenseoligonucleotides. The microparticles of the invention may in particularhave application in the administration of insulin to diabetic patients,preferably avoiding the normally invasive administration techniques usedfor that agent. The microparticles could also be used for pulmonaryadministration of other agents, for example, for pain relief (e.g.analgesics such as fentanyl or dihydroergotamine which is used for thetreatment of migraine), anti-cancer activity, anti-virals, antibioticsor the local delivery of vaccines to the respiratory tract.

The active substance is present in the form of particles and at leastsome of the hydrophobic material is present on the surfaces of thoseparticles of active substance. Such microparticles may be formed by drymixing together particles of active substance and particles ofhydrophobic substance or by combining particles of the hydrophobicsubstance with particles of active substance to form, in a liquid, asuspension, followed by the evaporation of the solvent to leave theparticles of hydrophobic material on the surface of the particles ofactive substance.

The terms “active particles” and “particles of active substance” areused interchangeably herein. The active particles referred to throughoutthe specification will comprise one or more pharmacologically activesubstances. The active particles will advantageously consist essentiallyof one or more pharmacologically active substances.

The hydrophobic material may be in the form of a coating on the surfacesof the active particles. The coating may be a discontinuous coating. Thehydrophobic material may be in the form of particles adhering to thesurfaces of the particles of the active material. Furthermore, asexplained above, at least some of the microparticles may be in the formof agglomerates.

The invention further provides a composition for inhalation comprisingmicroparticles as described above. Preferably, the composition is a drypowder and is suitable for use in a dry powder inhaler. Suchcompositions may comprise essentially only the microparticles or theymay comprise additional ingredients such as carrier particles andflavouring agents. Carrier particles may be of any acceptable excipientmaterial or combination of materials. For example, the carrier particlesmay consist substantially of one or more materials selected from sugaralcohols, polyols and crystalline sugars. Other suitable carriersinclude inorganic salts such as sodium chloride and calcium carbonate,organic salts such as sodium lactate and other organic compounds such aspolysaccharides and oligosaccharides. Advantageously, the carrierparticles are of a polyol. In particular the carrier particles mayconsist substantially of a crystalline sugar, for example mannitol,dextrose or lactose. Preferably, the carrier particles are of lactose.

Advantageously, substantially all (by weight) of the carrier particleshave a diameter which lies between 20 μm and 1000 μm, more preferably 50μm and 1000 μm. Preferably, the diameter of substantially all (byweight) of the carrier particles is less than 355 μm and lies between 20μm and 250 μm. Preferably at least 90% by weight of the carrierparticles have a diameter between from 60 μm to 180 μm. The relativelylarge diameter of the carrier particles improves the opportunity forother, smaller particles to become attached to the surfaces of thecarrier particles and to provide good flow and entrainmentcharacteristics and improved release of the active particles in theairways to increase deposition of the active particles in the lowerlung.

The ratio in which the carrier particles (if present) and microparticlesare mixed will, of course, depend on the type of inhaler device used,the active substance used and the required dose. The carrier particlesare preferably present in an amount of at least 50%, more preferably70%, advantageously 90% and most preferably 95% based on the combinedweight of the microparticles and the carrier particles.

Where carrier particles are included in the pharmaceutical composition,that composition preferably also includes small excipient particleshaving, for example, a particle size between 5 to 20 μm. Preferably thesmall excipient particles are present in an amount of from 1% to 40%,more preferably 5% to 20% based on the weight of the carrier particles.

The pharmaceutical composition may comprise a propellant and be suitablefor use in a pressurised metered dose inhaler. The microparticles willbe present as a suspension in the propellant and the composition mayinclude one or more surfactants known in the art for stabilising suchsuspensions.

The invention further provides a method of preparing microparticles foruse in a pharmaceutical composition for pulmonary administration, eachmicroparticle comprising an active substance and a hydrophobic materialsuitable for delaying the dissolution of the active substance, themethod comprising the step of combining the active substance with thehydrophobic material.

Preferably, as noted above, particles comprising the active substanceare combined with particles of the hydrophobic material. Preferably, theactive substance is milled in the presence of the hydrophobic material.

The word “milling” as used herein refers to any mechanical process whichapplies sufficient force to the particles of active material that it iscapable of breaking coarse particles (for example, particles of massmedium aerodynamic diameter greater than 100 μm) down to fine particlesof mass median aerodynamic diameter not more than 50 μm or which appliesa relatively controlled compressive force as described below in relationto the Mechano-Fusion and Cyclomix methods. It has been found thatprocesses such as blending which do not apply a high degree of force arenot effective in the method of the invention. It is believed that isbecause a high degree of force is required to separate the individualparticles of active material and to break up tightly bound agglomeratesof the active particles such that effective mixing and effectiveapplication of the hydrophobic material to the surfaces of thoseparticles is achieved. It is believed that an especially desirableaspect of the milling process is that the hydrophobic material maybecome deformed in the milling and may be smeared over or fused to thesurfaces of the active particles. It should be understood, however, thatin the case where the particles of active material are already fine, forexample, having a mass median aerodynamic diameter below 20μ prior tothe milling step, the size of those particles may not be significantlyreduced. The important thing is that the milling process applies asufficiently high degree of force or energy to the particles.

The method of the invention generally involves bringing the particles ofhydrophobic material into close contact with the surfaces of the activeparticles. In order to achieve coated particles, a degree of intensivemixing is required to ensure a sufficient break-up of agglomerates ofboth constituents, dispersal and even distribution of additive over thehost active particles.

Where the particles of hydrophobic material are very small (typically <1micron), generally less work is required, firstly, as it is not requiredto break or deform but only to deagglomerate, distribute and embed theadditive particles onto the active particle and, secondly, because ofthe naturally high surface energies of such small particles ofhydrophobic material. It is known that where two powder components aremixed and the two components differ in size, there is a tendency for thesmall particles to adhere to the large particles (to form so called‘ordered mixes’). The short range Van der Waals interactions for suchvery fine components may be sufficient to ensure adhesion. However,where both the particles of hydrophobic material and active particlesare very fine (for example less than 5 microns) a substantial degree ofmixing will be required to ensure a sufficient break-up of agglomeratesof both constituents, dispersal and even distribution of additiveparticles over the active particles as noted above. In some cases asimple contact adhesion may be insufficient and a stronger embedding orfusion of particles of hydrophobic material onto active particles isrequired to prevent segregation, or to enhance the structure andfunctionality of the coating.

Where the particles of hydrophobic material are not so small as to besufficiently adhered by Van der Waals forces alone, or where there areadvantages to distorting and/or embedding the particles of hydrophobicmaterial substantially onto the host active particle, a greater degreeof energy is required from the milling. In this case, the particles ofhydrophobic material should experience sufficient force to soften and/orbreak, to distort and to flatten them. These processes are enhanced bythe presence of the relatively harder active particles which act as amilling media as well as a de-agglomerating media for such processes. Asa consequence of this process the particles of hydrophobic material maybecome wrapped around the core active particle to form a coating. Theseprocesses are also enhanced by the application of a compression force asmentioned above.

As a consequence of the milling step, complete or partial, continuous ordiscontinuous, porous or non-porous coatings may be formed. The coatingsoriginate from a combination of active particles and particles ofhydrophobic material. They are not coatings such as those formed by wetprocesses that require dissolution of one or both components. Ingeneral, such wet coating processes are likely to be more costly andmore time consuming than the milling process and also suffer from thedisadvantage that it is less easy to control the location and structureof the coating.

A wide range of milling devices and conditions are suitable for use inthe method of the invention. The milling conditions, for example,intensity of milling and duration, should be selected to provide therequired degree of force. Ball milling is a preferred method.Centrifugal and planetary ball milling are especially preferred methods.Alternatively, a high pressure homogeniser may be used in which a fluidcontaining the particles is forced through a valve at high pressureproducing conditions of high shear and turbulence. Shear forces on theparticles, impacts between the particles and machine surfaces or otherparticles and cavitation due to acceleration of the fluid may allcontribute to the fracture of the particles and may also provide acompressive force. Such homogenisers may be more suitable than ballmills for use in large scale preparations of the composite activeparticles. Suitable homogensiers include EmulsiFlex high pressurehomogenisers which are capable of pressure up to 4000 Bar, Niro Soavihigh pressure homogenisers (capable of pressures up to 2000 Bar), andMicrofluidics Microfluidisers (maximum pressure 2750 Bar). The millingstep may, alternatively, involve a high energy media mill or an agitatorbead mill, for example, the Netzch high energy media mill, or theDYNO-mill (Willy A. Bachofen AG, Switzerland). Alternatively the millingmay be a dry coating high energy process such as a Mechano-Fusion system(Hosokawa Micron Ltd) or a Hybridizer (Nara). Other possible millingdevices include air jet mills, pin mills, hammer mills, knife mills,ultracentrifugal mills and pestle and mortar mills.

Especially preferred methods are those involving the Mechano-Fusion,Hybridiser and Cyclomix instruments.

Preferably, the milling step involves the compression of the mixture ofactive particles and particles of hydrophobic material in a gap (or nip)of fixed, predetermined width (for example, as in the Mechano-Fusion andCyclomix methods described below).

Some preferred milling methods will now be described in greater detail.

Mechano-Fusion:

As the name suggests, this dry coating process is designed tomechanically fuse a first material onto a second. The first material isgenerally smaller and/or softer than the second. The Mechano-Fusion andCyclomix working principles are distinct from alternative millingtechniques in having a particular interaction between inner element andvessel wall, and are based on providing energy by a controlled andsubstantial compressive force.

The fine active particles and the particles of hydrophobic particles arefed into the Mechano-Fusion driven vessel, where they are subject to acentrifugal force and are pressed against the vessel inner wall. Thepowder is compressed between the fixed clearance of the drum wall and acurved inner element with high relative speed between drum and element.The inner wall and the curved element together form a gap or nip inwhich the particles are pressed together. As a result the particlesexperience very high shear forces and very strong compressive stressesas they are trapped between the inner drum wall and the inner element(which has a greater curvature than the inner drum wall). The particlesviolently collide against each other with enough energy to locally heatand soften, break, distort, flatten and wrap the particles ofhydrophobic material around the core particle to form a coating. Theenergy is generally sufficient to break up agglomerates and some degreeof size reduction of both components may occur. Embedding and fusion ofparticles of hydrophobic material onto the active particles may occur,facilitated by the relative differences in hardness (and optionallysize) of the two components. Either the outer vessel or the innerelement may rotate to provide the relative movement. The gap betweenthese surfaces is relatively small, and is typically less than 10 mm andis preferably less than 5 mm, more preferably less than 3 mm. This gapis fixed, and consequently leads to a better control of the compressiveenergy than is provided in some other forms of mill such as ball andmedia mills. Also, preferably, no impaction of milling media surfaces ispresent so that wear and consequently contamination are minimised. Thespeed of rotation may be in the range of 200 to 10,000 rpm. A scrapermay also be present to break up any caked material building up on thevessel surface. This is particularly advantageous when using finecohesive starting materials. The local temperature may be controlled byuse of a heating/cooling jacked built into the drum vessel walls. Thepowder may be re-circulated through the vessel.

Cyclomix Method (Hosokawa Micron):

The Cyclomix comprises a stationary conical vessel with a fast rotatingshaft with paddles which move close to the wall. Due to the highrotational speed of the paddles, the powder is propelled towards thewall, and as a result the mixture experiences very high shear forces andcompressive stresses between wall and paddle. Such effects are similarto the Mechano-Fusion as described above and may be sufficient tolocally heat and soften, to break, distort, flatten and wrap theparticles of hydrophobic material around the active particles to form acoating. The energy is sufficient to break up agglomerates and somedegree of size reduction of both components may also occur depending onthe conditions and upon the size and nature of the particles.

Hybridiser Method:

This is a dry process which can be described as a product embedding orfilming of one powder onto another. The fine active particles and fineor ultra fine particles of hydrophobic material are fed into aconventional high shear mixer pre-mix system to form an ordered mixture.This powder is then fed into the Hybridiser. The powder is subjected toultra-high speed impact, compression and shear as it is impacted byblades on a high speed rotor inside a stator vessel, and isre-circulated within the vessel. The active particles and particles ofhydrophobic material collide with each other. Typical speeds of rotationare in the range of 5,000 to 20,000 rpm. The relatively soft fineadditive particles experience sufficient impact force to soften, break,distort, flatten and wrap around the active particle to form a coating.There may also be some degree of embedding into the surface of theactive particles.

Other preferred methods include ball and high energy media mills whichare also capable of providing the desired high shear force andcompressive stresses between surfaces, although as the clearance gap isnot controlled, the coating process may be less well controlled than forMechano-Fusion milling and some problems such as a degree of undesiredre-agglomeration may occur. These media mills may be rotational,vibrational, agitational, centrifugal or planetary in nature.

It has been observed in some cases that when ball milling activeparticles with hydrophobic material, a fine powder is not produced.Instead the powder was compacted on the walls of the mill by the actionof the mill. That has inhibited the milling action and prevented thepreparation of the microparticles. That problem occurred particularlywhen certain hydrophobic materials were used, in cases where thehydrophobic material was present in small proportions (typically <2%),in cases where the milling balls were relatively small (typically <3mm), in cases where the milling speed was too slow and where thestarting particles were too fine. To prevent this occurring it isadvantageous to ball mill in a liquid medium. The liquid medium reducesthe tendency to compaction, assists the dispersal of hydrophobicmaterial and improves any milling action.

It has been found to be preferable to use a large number of fine millingballs, rather than fewer heavy balls. The finer balls perform a moreefficient co-milling action. Preferably the balls have a diameter ofless than 5 mm, advantageously less than 2 mm. Liquid media arepreferred which do not dissolve the active material and which evaporaterapidly and fully, for example non-aqueous liquids such as diethylether,acetone, cyclohexane, ethanol, isopropanol or dichloromethane. Liquidmedia are preferred which are non flammable, for example dichloromethaneand fluorinated hydrocarbons, especially fluorinated hydrocarbons whichare suitable for use as propellants in inhalers.

Pestle and mortar mills are other mills which also provide a very highshear force and compressive stresses between surfaces.

Mechano-Micros and Micros mills made by Nara (where particles arecompressed by rotating grinding rings) may also be used. Mills referredto as impact mixers, attrition mills, pin mills and disc mills may alsobe used.

The mass median aerodynamic diameter of the particles of active materialmay be substantially reduced during the milling step especially when theactive material is in the form of coarse particles prior to the millingstep. The mass median aerodynamic diameter (MMAD) of the particles ofactive material may be reduced by at least 10%, by at least 50%, or byat least 70% during the milling step depending on the milling conditionsand the MMAD of the active particles prior to the milling step.

Advantageously, after the milling step, the MMAD of the active particlesis less than 9 μm, preferably less then 4 μm and more preferably lessthen 2 μm.

In a similar way, where the hydrophobic material is in the form ofcoarse particles prior to the milling step, their MMAD will besubstantially reduced during the milling step. The MMAD of the particlesof hydrophobic material may be reduced by at least 10%, at least 50% orat least 70% during the milling step, depending on the millingconditions and on the MMAD of the particles of hydrophobic materialbefore the milling step.

The size of the particles of hydrophobic material after the milling stepis preferably significantly less than the size of the active particles,to enable the hydrophobic materials to more effectively coat thesurfaces of the active particles. In practice, that difference in sizebetween the active particles and particles of hydrophobic material willbe achieved as a consequence of the milling because the hydrophobicmaterial will usually be more easily fractured or deformed than theactive material and so will be broken into smaller particles than theactive material. As noted above, the particles of hydrophobic materialpreferably become smeared over or fused to the surfaces of the particlesof active material, thereby forming a coating which may be substantiallycontinuous or discontinuous. Where the coating is discontinuous, itpreferably covers on average of at least 50% (that is, at least 50% ofthe total surface area of the active particles will be covered byadditive material), more advantageously at least 70% and most preferablyat least 90% of the surfaces of the active particles. The coating ispreferably on average less than 1 μm, more preferably less than 0.5 μmand most preferably less than 200 nm thick.

The milling step may be carried out in a closed vessel, for example in aball mill or a Mechano-Fusion device. The use of a closed vesselprevents loss of ultrafine particles or vapour of the hydrophobicmaterial which has been found to occur in jet milling or other openprocesses. Preferably, the milling is not jet milling (micronisation).

The milling may be wet milling, that is, the milling step may be carriedout in the presence of a liquid. That liquid medium may be high or lowvolatility and of any solid content as long as it does not dissolve theactive particles to any significant degree and its viscosity is not sohigh that it prevents effective milling. The liquid medium preferably isnot aqueous. The liquid is preferably one in which the hydrophobicmaterial is substantially insoluble but some degree of solubility may beacceptable as long as there is sufficient hydrophobic material presentthat undissolved particles of hydrophobic material remain. The presenceof a liquid medium helps to prevent compacting of the particles ofactive material on the walls of the vessel and may also allow the moreeven spreading of the hydrophobic material on the surface of theparticles of active material as compared to dry milling.

It has been found that the Mechano-Fusion and Cyclomix techniquesreferred to above often provide the microparticles as individual, thatis, unagglomerated microparticles. That is in contrast to lesscontrolled methods such as ball milling, which have been found to oftenproduce the microparticles in the form of agglomerated microparticles.

Alternatively, particles comprising the active substance are combinedwith the particles of hydrophobic material in a spray drying step, thatis, by spray drying a suspension comprising the particles of activesubstance and particles of hydrophobic substances. The film formingmaterial, if present, will be dissolved in the suspension. The skilledperson will be able to select appropriate spray drying conditions. Anumber of commercially available spray drying machines can be used toprepare the microparticles of the invention, for example, suitablemachines are manufactured by Buchi and Niro. In a typical spray dryingmachine the suspension to be dried is pumped from a stirred reservoir toan atomisation chamber where it is sprayed from a nozzle as finedroplets (preferably the droplets are in the range of 1 to 20 μm indiameter) into a stream of heated air, for example, inlet temperaturesin the range of 50 to 150° C. (nitrogen can be used in place of air ifthere is a risk of undesirable oxidation of the active substance). Thetemperature of the heated air must be sufficient to evaporate the liquidand dry the microparticles to a free flowing powder but should not be sohigh as to degrade the active substance. The microparticles may becollected in a cyclone or a filter or a combination of cyclones andfilters.

The invention also provides a method of pulmonary administration of anactive substance comprising the step of administering microparticles asdescribed above to a person in need thereof.

The invention also provides the use of a hydrophobic material in apharmaceutical composition comprising an active substance for pulmonaryadministration, to delay the dissolution of the active substance in thelung. Preferably, the use of the hydrophobic substance reduces the rateof dissolution of the active substance by at least 20%, preferably atleast 30% and more preferably by at least 50%.

According to a further aspect of the invention, a pharmaceuticalcomposition for pulmonary delivery comprises an active substance thatexerts a pharmacological effect over a period less than 12 hours, in adelayed release formulation, wherein, on administration, the formulationpermits the active substance to exert its pharmacological effect over aperiod greater than 12 hours.

The delayed release formulation will preferably comprise or consist ofmicroparticles as described above.

Embodiments of the invention will now be described for the purposes ofillustration only with reference to the Figures in which:

FIG. 1 shows an apparatus used in the dissolution test;

FIG. 2 shows the results of the dissolution test on the formulations ofExample 3;

FIG. 3 shows dissolution curves for salbutamol sulphate and salbutamolsulphate/magnesium stearate blends;

FIG. 4 shows dissolution curves for sieved and unsieved blends ofsalbutamol sulphate and magnesium stearate;

FIG. 5 is a schematic drawing of part of a Mechano-Fusion machine; and

FIGS. 6 and 7 are electron micrographs of composite active particlesaccording to the invention comprising salbutamol sulphate and magnesiumstearate in a ratio of 19:1.

EXAMPLE 1a

5 g of micronised salbutamol sulphate (particle size distribution: 1 to5 μm) and 0.5 g of magnesium stearate were added to a 50 cm³ stainlesssteel milling vessel together with 20 cm³ dichloromethane and 124 g of 3mm stainless steel balls. The mixture was milled at 550 rpm in a RetschS100 Centrifugal Mill for 5 hours. The powder was recovered by dryingand sieving to remove the mill balls. The powders were examined using ascanning electron microscope and were found to have particles in thesize range 0.1 to 0.5 μm.

EXAMPLE 1b

Micronised salbutamol sulphate and magnesium stearate were combined asparticles in a suspension in the ratio 10:1 in propanol. This suspensionwas processed in an Emulsiflex C50 high pressure homogeniser by 5sequential passes through the system at 25,000 psi. This dry materialwas then recovered by evaporating the propanol.

EXAMPLE 1c

It was found that, on drying, the powder prepared in Example 1aincluding magnesium stearate as additive material formed assemblies ofprimary particles which were hard to deagglomerate. A sample of thispowder was re-dispersed by ball milling for 90 minutes at 550 rpm in amixture of ethanol, polyvinylpyrrolidone (PVPK30) and HFA227 liquidpropellant to give the following composition:

0.6% w/w Salbutamol sulphate/magnesium stearate microparticles 0.2% w/wPVPK30 5.0% w/w Ethanol 94.2% w/w  HFA 227 (The PVP was included tostabilise the suspension of the microparticles in the ethanol/HFA227).

The composition was sprayed from a pressurised can through an orifice˜0.4 mm in diameter to produce dried microparticles of salbutamolsulphate and magnesium stearate with PVP. Those particles were collectedand examined and were found to be in the aerodynamic size range 0.1 to 4μm.

EXAMPLE 2

The process of Example 1c was repeated except that the composition wasas follows:

3% w/w Salbutamol sulphate/magnesium stearate microparticles 1% w/wPVPK30 3% w/w Ethanol 93% w/w  HFA 227

Similarly, a sample was redispersed in dichloromethane and spray dried.

EXAMPLE 3

A mixture of micronised glycopyrrolate and magnesium stearate in theratio 75:25 by mass (total mass of approximately 1 g) was placed in aball mill on top of 100 g of 2 mm stainless steel balls. The mill volumewas approximately 58.8 cm³. 5 cm³ of cyclohexane was added to wet themixture. The mill was sealed and secured in a Retsch S100 centrifuge.Centrifugation was then carried out at 500 rpm for 240 minutes in total.Small samples (approximately 5-10 mg) of wet powder were then removedfrom the mill every 60 minutes. The samples were dried in an oven at 37°C. under a vacuum, prior to using the samples in the dissolution test.

The samples were analysed in a Cecil Aquarius CE7200 ultravioletspectrophotometer at a wavelength of 200 nm. The concentration of thesamples was calculated with a previously prepared calibration graph andthe concentration versus time was plotted. To establish the base linediffusion characteristics of the system, 1 cm³ aqueous solutioncontaining 1 mg of glycopyrrolate was added to the system and thesamples taken as above. The results are shown in FIG. 2.

FIG. 2 shows that the sample containing only glycopyrrolate exhibited aquick release of the glycopyrrolate into the reservoir, with the firsttime point at 5 minutes showing a concentration of greater than 10 mg/l.In contrast, the glycopyrrolate/magnesium stearate composition showedthe delayed release properties, with a concentration at 5 minutes ofapproximately 3.7 mg/l. The maximum concentration is achieved after 40minutes in contrast to that of glycopyrrolate only, which achieves themaximum concentration at only 10 minutes.

EXAMPLE 4 Salbutamol Sulphate/Magnesium Stearate Blends a) HomogenisedMagnesium Stearate

240 g magnesium stearate (Riedel de Haen, particle size by Malvern laserdiffraction: d₅₀=9.7 μm) was suspended in 2150 g dichloroethane. Thatsuspension was then mixed for 5 minutes in a Silverson high shear mixer.The suspension was then processed in an Emulsiflex C50 high pressurehomogeniser fitted with a heat exchanger at 10000 psi for 20 minutes incirculation mode (300 cm³/min) for 20 minutes. The suspension was thencirculated at atmospheric pressure for 20 minutes allow it to cool. Thenext day, the suspension was processed in circulation mode (260 cm³/min)at 20000 psi for 30 minutes.

The dichloroethane was removed by rotary evaporation followed by dryingin a vacuum over at 37° C. overnight. The resulting cake of material wasbroken up by ball milling for 1 minute. The homogenised magnesiumstearate had a particle size of less than 2 μm.

b) A 9:1 by weight blend of salbutamol sulphate and homogenisedmagnesium stearate having a particle size of less than 2 μm was preparedby blending the two materials with a spatula. An electron micrograph ofthe blended material showed that the blend was mostly in the form ofagglomerated particles, the agglomerates having diameters of 50 μm andabove. The blend was then processed in a Mechano-Fusion mill (Hosokawa)as follows:

Machine data: Hosokawa Mechano-Fusion: AMS-Mini Drive: 2.2 kW Housing:stainless steel Rotor: stainless steel Scraper: None Cooling: Water Gaspurge: None

The Mechano-Fusion device (see FIG. 5) comprises a cylindrical drum 1having an inner wall 2. In use, the drum rotates at high speed. Thepowder 3 of the active and additive particles is thrown by centrifugalforce against the inner wall 2 of the drum 1. A fixed arm 4 projectsfrom the interior of the drum in a radial direction. At the end of thearm closest to the wall 2, the arm is provided with a member 5 whichpresents an arcuate surface 6, of radius of curvature less than that ofinner wall 2, toward that inner wall. As the drum 1 rotates, it carriespowder 3 into the gap between arcuate surface 6 and inner wall 2 therebycompressing the powder. The gap is of a fixed, predetermined width A. Ascraper (not shown in FIG. 5) may be provided to scrape the compressedpowder from the wall of the drum.

All samples were premixed for 5 minutes by running the machine at 1000rpm. The machine speed was then increased to 5050 rpm for 30 minutes.The procedure was repeated for salbutamol sulphate/magnesium stearate inthe following weight ratios: 19:1, 3:1, 1:1.

Electronmicrographs of the 19:1 processed material are shown in FIGS. 6and 7 and indicate that the material was mostly in the form of simplesmall particles of diameter less than 5 μm or in very loose agglomeratesof such particles with only one agglomerate of the original type beingvisible.

The 3:1 and the 19:1 blends were then each loaded into a 20 mg capsuleand fired from a twin stage impinger. A sample of unprocessed salbutamolsulphate was also fired from the TSI to provide a comparison.

The fine particle fractions were then calculated and are given in table1.

TABLE 1 Fine Particle Fraction results for salbutamol sulphate blends.Composition Fine Particle Fraction % salbutatmol sulphate 28 salbutamolsulphate/magnesium 66 stearate 19:1 salbutamol sulphate/magnesium 66stearate 3:1

A 1 g sample of the 3:1 blend was suspended by ball milling in 10 cm³dichloromethane for 5 minutes. The suspension was then spray dried on aBuchi B191 spray dryer using the following conditions inlet T=50° C.,aspirator 100%, liquid flow 10 cm³/min nozzle air flow 800 cm³/hr. The3:1 blend, the spray dried 3:1 blend and a sample of salbutamol sulphatewere then each tested for dissolution rate using the procedure outlinedabove. The results are shown in FIG. 3. It is clear from FIG. 3 that the3:1 blend of salbutamol sulphate:magnesium stearate dissolves at asignificantly slower rate than the salbutamol sulphate with no magnesiumstearate. That delayed dissolution effect is shown by the spray driedsample of the 3:1 blend. That contrasts to the results of similarexperiments carried out using blends of drug and magnesium stearatewhere the magnesium stearate has not been homogenised (and does not havea particle size below 2 μm) in which spray drying of the blend hasproduced a significant decrease in the extent of the delayed dissolutioneffect.

To test the effect of any agglomeration in the blend upon thedissolution rate of the salbutamol sulphate in the blends a sample ofthe 3:1 salbutamol sulphate:magnesium stearate blend was brushed througha 45 μm sieve. FIG. 4 shows the dissolution curves for the sieved andunsieved blends and for salbutamol sulphate. It can be seen that thesieved and unsieved 3:1 blends had the same dissolution rate.

1) Standard Dissolution Test

This test is used as a model test for the length of time taken for aparticular formulation to dissolve on the lung membrane.

The apparatus used is shown in FIG. 1 and comprises a 195 cm³ reservoir(1) filled with deionised water (2) and having an inlet port (3) and anoutlet port (4). A sintered glass disc (5) of approximately 50 mmdiameter and 3 mm depth occupies an opening at the top of the reservoir(1) and sits horizontally in contact with the water (2). The water inthe reservoir is stirred by a magnetic stirrer (6).

A known mass of approximately 1 mg of the formulation (7) to be testedis placed on the sinter and a timer is started. At various times, 1 cm³samples of the water are removed from the reservoir and are immediatelyreplaced with 1 cm³ deionised water to maintain the volume in thereservoir. The concentration of the active substance in the 1 cm³samples is determined by a suitable method. The particular method will,of course, depend on the nature of the active substance but such methodswill be known to the skilled person.

A graph of concentration of the active substance in the reservoir ofwater versus time is then plotted.

2) Standard Formulation Test

In order to determine whether or not a particular hydrophobic materialis suitable for delaying the dissolution of the active substance, thefollowing test is carried out.

A standard test formulation is prepared in the following manner:

A mixture of salbutamol sulphate and the material to be tested in theratio of 75:25 by mass (total mass of approximately 1 g) is placed in aball mill chamber on top of 100 g of 2 mm diameter stainless steelballs. The mill chamber volume is approximately 58.8 cm³. 5 cm³ of aninert non-solvent is added to wet the mixture. The mill is sealed andsecured in a Retsch S100 centrifuge. Centrifugation is then carried outat 500 rpm for 240 minutes in total. A small sample (approximately 5-10mg) of wet powder is removed from the mill after 60 minutes. The sampleis then dried in an oven at 37° C. under vacuum for 2 hours or as longas necessary to remove the inert non-solvent.

Where the hydrophobic material is such that no suitable non-solvent canbe found, the mixture of salbutamol sulphate and the hydrophobicmaterial is combined in a Mechano-Fusion apparatus as described above inexample 4b).

The dry powder is then tested using the standard dissolution test givenabove.

The procedure is repeated using the active substance in the absence ofthe hydrophobic material in order to provide a basis for comparison. Theresulting dried active substance is then tested using the standarddissolution test.

If the graph of concentration versus time for the active substancecombined with the hydrophobic material shows that that active substancein that combination has dissolved more slowly than the active substancealone, the hydrophobic material is regarded as being suitable fordelaying the dissolution of the active substance.

The degree to which the hydrophobic material delays the dissolution ofthe active substance is a measure of the efficiency of the hydrophobicmaterial. In particular, where it is desired to measure the delayedrelease performance of a particular formulation, that can be done bycarrying out the standard dissolution test given above on a sample ofthe microparticles to be tested and upon a (control) sample of theactive substance. For a true comparison the particle size distributionof the particles of the active substance must be the same or similar inthe sample of formulation to be tested as in the (control) sample ofactive substance. The rate of dissolution of the active substance in themicroparticles to be tested as a percentage of the rate of dissolutionof the active substance alone can then be calculated by the followingformula:

${\% \mspace{14mu} {rate}\mspace{14mu} {of}\mspace{14mu} {dissolution}} = {\frac{TA}{TF} \times 100}$

-   Where TA=time taken for the concentration of the active substance to    reach a maximum for the sample of active substance alone.-   Where TF=time taken for the concentration of the active substance to    reach a maximum for the sample of the formulation to be tested.    Thus, for example, if the concentration of the active substance in    the dissolution test on the formulation reached a maximum at 40    minutes and the concentration of the active substance alone reached    a maximum at 10 minutes, the % rate of dissolution for the    formulation would be 10/40×100=25%, corresponding to a decrease in    the rate of dissolution of 75%.    An alternative method is to measure the contact angle. Additive    materials having contact angles greater than 90 are also regarded as    hydrophobic additive materials.

What is claimed:
 1. Microparticles for use in a pharmaceuticalcomposition for pulmonary administration, comprising particles of anactive substance having, on their surfaces, particles of a hydrophobicmaterial suitable for delaying the dissolution of the active substance.2. Microparticles according to claim 1 wherein the hydrophobic materialcomprises a C₁₀ to C₂₂ carboxylic acid which may be linear or branched,saturated or unsaturated or a derivative thereof.
 3. Microparticlesaccording to claim 2 wherein the hydrophobic material comprisesmagnesium stearate.
 4. Microparticles according to claim 1 in which thehydrophobic material comprises a phospholipid.
 5. Microparticlesaccording to claim 1 which comprise not more than 90% of the hydrophobicmaterial based on the total weight of the microparticles. 6.Microparticles according to claim 1 having a mass median aerodynamicdiameter of not more than 10 μm.
 7. Microparticles as claimed in claim 1to 6 which are in the form of agglomerated microparticles. 8.Microparticles as claimed in claim 1 which have at least a partialcoating of a film-forming material.
 9. Microparticles as claimed inclaim 1 being such that, upon inhalation of the microparticles, theactive substance exerts its pharmacological effect over a periodsignificantly greater than the period over which the active substanceexerts its pharmacological effect when inhaled alone.
 10. Microparticlesas claimed in claim 1 comprising an active substance which dissolvesrapidly under the conditions obtaining in the lung.
 11. Microparticlesas claimed in claim 1 having a rate of dissolution no greater than 80%of the rate of dissolution of particles of the active substance. 12.Microparticles as claimed in claim 1 which do not comprise an effectiveamount of an antimuscarinic agent.
 13. Microparticles as claimed inclaim 1 in which the particles of hydrophobic material are present as acoating on the surfaces of the particles of active substance. 14.Microparticles as claimed in claim 13 in which the coating is adiscontinuous coating.
 15. Microparticles as claimed in claim 1 whichare suitable for use in a powder for use in a dry powder inhaler.
 16. Acomposition for inhalation comprising microparticles as claimed inclaim
 1. 17. A composition as claimed in claim 16 which is a dry powderand is suitable for use in a dry powder inhaler.
 18. A composition asclaimed in claim 17 which comprises carrier particles.
 19. A compositionas claimed in claim 16 which comprises a propellant and is suitable foruse in a pressurised metered dose inhaler.
 20. A method of preparingmicroparticles for use in a pharmaceutical composition for pulmonaryadministration, comprising particles of active substance having, ontheir surfaces, particles of a hydrophobic material suitable fordelaying the dissolution of the active substance, the method comprisingthe step of combining particles of the active substance with particlesof the hydrophobic material.
 21. A method as claimed in claim 20 inwhich particles of the active substance are milled in the presence ofthe particles of the hydrophobic material.
 22. A method according toclaim 21 in which the milling step involves ball milling.
 23. A methodaccording to claim 21 in which the milling step involves passing amixture of particles of hydrophobic material and particles of activematerial, in a liquid, through a constriction under pressure.
 24. Amethod according to claim 21 in which the milling step involvescompressing a mixture of the active particles and particles ofhydrophobic material in a gap of predetermined width.
 25. A method asclaimed in claim 20 in which particles comprising the active substanceare combined with the hydrophobic material in a spray drying step.
 26. Amethod of pulmonary administration of an active substance comprising thestep of administering a composition as claimed in claims- to 49 to aperson in need thereof.
 27. Use of a hydrophobic material in apharmaceutical composition comprising an active substance for pulmonaryadministration, to delay the dissolution of the active substance in thelung.
 28. Use as claimed in claim 27 in which the rate of dissolution isreduced by at least 20%.
 29. (canceled)
 30. (canceled)
 31. (canceled)32. A method of preparing microparticles exhibiting delayed dissolutionfor use in a pharmaceutical composition for pulmonary administration,comprising the step of combining particles of an active substance withparticles of a hydrophobic material in a spray drying step.
 33. Themethod as claimed in claim 32, in which the spray-drying step involvesspray-drying a suspension comprising the particles of active substanceand the particles of hydrophobic material.
 34. The method as claimed inclaim 33, in which a film-forming material is dissolved in thesuspension.
 35. The method as claimed in claim 32, wherein the dropletsformed during the spray-drying process are in the range of 1-20 μm indiameter.
 36. The method as claimed in claim 32, wherein the inlettemperature in the spray drying step is in the range of 50-150° C.